DevelopmentalOriginsofHealth...
Transcript of DevelopmentalOriginsofHealth...
Developmental Origins of Health and Disease: A new perspec9ve on Fetal Alcohol Spectrum Disorder JOANNE WEINBERG, PHD DEPARTMENT OF CELLULAR & PHYS IOLOGICAL SC IENCES
UN IVERS ITY OF BR IT ISH COLUMBIA
7 T H NAT IONA L B I ENN I A L CONF ER ENCE ON ADO L E S C ENT S AND
A DU LT S W I TH FA SD A P R I L 6 -‐ 9 , VANCOUVER , B C
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This presenta,on may not be copied or used in any way without specific permission from Dr. Joanne Weinberg
Learning Objec9ves • Describe the adverse health outcomes in individuals with FASD
• Explain how prenatal alcohol exposure could act on the fetus to increase vulnerability to later life diseases/disorders
• Explain what types of interven,ons might be possible to aDenuate some of the adverse health outcomes observed in FASD
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Adverse effects of prenatal alcohol exposure on long-‐term health outcomes:
Clinical evidence and data from animal models
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Dose-‐Response Curve for Teratogens As dose increases, more fetuses at risk, effects more severe
(From Jacobson & Jacobson, Alcohol Health & Research World 18:30-‐36, 1994)
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Vulnerability at Different Developmental Periods (From Coles, Alcohol Health & Research World 18:22-‐29, 1994)
Weinberg 2016 Of note, the brain develops throughout gesta,on and into postnatal life.
A Developmental Origins of Health and Disease (DOHaD) Framework
§ NIAAA Program Announcement: ◦ Fetal adapta,ons in response to adverse intrauterine condi,ons may increase the risk for diseases or disorders across the lifespan
◦ At this ,me, the impact of prenatal alcohol exposure on the development of adult-‐onset disease and health condi,ons is largely unknown
◦ Understanding how exposure of the embryo and fetus to alcohol may alter health and chronic disease later in life represents a significant public health concern and warrants inves,ga,on
§ The DOHaD framework is rela,vely new to the FASD field. But it provides an extremely important approach for understanding later life outcomes and for developing appropriate interven,ons
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Data from clinical studies to date
§ Numerous structural/func,onal abnormali,es that will impact health and well-‐being1,2,3 o Cardiac anomalies o Urinary and kidney anomalies o Neural tube defects o CleU lip with or without cleU palate o Gastrointes,nal and genital abnormali,es o Dental anomalies o Limb and joint abnormali,es, scoliosis o Eye abnormali,es -‐ ptosis, strabismus, epicanthal folds, microphthalmia,
myopia
§ Increased risk of preterm birth4
§ Decreased immune cells counts (eosinophils, neutrophils) and response to s,mula,on5
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Data from clinical studies to date § Higher incidence of minor infec,ons (recurrent ear and respiratory) and major/life-‐threatening infec,ons (early-‐onset sepsis in very low birth weight alcohol-‐exposed newborns)5,6 o Likely due to deficits in immune func,on of both infant and mother o Level of alcohol intake important factor in predic,ng neonatal infec,on risk
§ Increased incidence of certain types of cancer (neuroblastoma, leukemia) -‐ possibly related to compromised immune status7,8
§ Altera,ons in maternal immune func,on with alcohol consump,on6,9,10 programming effects on developing fetus: o Altered cytokine levels in maternal circula,on (Chambers et al and the CIFASD,
preliminary data) -‐ implica,ons for offspring brain, physiological, cogni,ve, behavioral, immune development
§ Func,onal abnormali,es of the kidney11 o Impairment in renal acidifica,on and potassium excre,on, defect in urinary
concentra,ng ability, even in the absence of any structural abnormali,es.
§ Mental Health problems12,13 o Occur in ~ 94% of individuals with FASD o Depression (50%), ADHD/ADD (42%), anxiety/panic aDacks (38%)
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Causes of death for people with FAS14
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Why Use animal models?
§ Control of environmental variables o Dose, ,ming of exposure, other drugs, maternal nutri,on
and health, prenatal/postnatal environment
§ Control of gene,c variables o Gene,c differences in vulnerability or sensi,vity to the
same dose of alcohol o Gene,c differences in absorp,on, distribu,on,
metabolism, elimina,on of alcohol o Separate gene,c from environmental effects
§ Insight into mechanisms of ac,on can suggest strategies for interven,on (pregnant females) and treatment (exposed offspring)
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Cellular and molecular mechanisms of alcohol’s teratogenic effects
§ The varying paDerns observed in children with FASD suggest mul,ple mechanisms, likely ac,vated at different stages of development or at different dose thresholds of exposure
§ Mul,level analyses needed as we collect data on adverse health outcomes in rela,on to FASD. o Can we get enough informa,on on dose, ,ming, level of exposure o Can we get good informa,on on prenatal/early life environments? o Can we begin to separate effects of alcohol from effects of adverse early
life environments?
§ Understanding mechanisms can allow for targeted interven,ons and have policy implica,ons o Need to consider both direct (neuronal cell damage/death, inhibi,on of protein/DNA synthesis) and indirect (nutri,on, placenta dysmorphology, vascular, oxida,ve stress/free radicals, growth factors, hormones, cell signaling, cell adhesion, epigene,cs [changes in gene expression]) effects
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Data from animal models § Many organ systems show adverse effect of prenatal alcohol exposure on structure and func,on o Pancreas abnormali,es: structural changes, adiposity, glucose intolerance, pre-‐diabe,c insulin insensi,vity, insulin func,on15-‐18
o Heart problems – changes indica,ve of leU ventricular hypertrophy following chronic low dose alcohol during gesta,on; adverse effects on heart muscle; smaller volume of heart cells; impaired neural control of heart rate19,20
o Changes in fetal and postnatal lung: impaired and delayed growth and development, decreased surfactant, cellular changes sugges,ve of pulmonary fibrosis, changes in immune cells in lung (disrup,on of alveolar macrophage ac,vity -‐ deficits in clearing infec,ous agent)21-‐25
o Adverse effects on offspring kidney and blood pressure: decreased nephron numbers – implica,ons for cardiovascular health, blood pressure26-‐28
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Data from animal models § Altered mammary gland development and increased tumor suscep,bility, altered tumor phenotype29-‐33
§ Increased suscep,bility to osteoarthri,s34
§ Deficits in immune func,on and increased inflamma,on35,36 o Deficits in immune cell responses to s,mula,on (mitogens and alcohol) o Altered immune func,on in the neonatal period – a “pro-‐inflammatory” bias
o Increased severity and dura,on of immune ac,vity or inflamma,on in response to challenge in adulthood – increased severity and dura,on of arthri,s, increased inflamma,on following “bacterial” challenge
§ Increased vulnerability to depressive-‐ and anxiety-‐like behavior37
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Insights from Animal models § Animal models mirror many of the health problems, diseases and disorders seen in children with FASD
§ If these health problems, diseases, disorders can be reproduced in an animal model under controlled condi,ons -‐ dose, ,ming of exposure, other drugs, maternal nutri,on and health, prenatal/postnatal environment, gene,cs § Then are these secondary disabili1es as they have been called previously? § Or are they primary problems, or at least have a primary component, and based largely on the effects of alcohol?
§ No doubt that problems may be exacerbated by adverse prenatal/early life environments, but they are not necessarily due to environmental causes
§ In the real world, many children with FASD also experience early life stress and adversity, and stress/adversity may some,mes con,nue into childhood or adolescence.
§ Early life stress/adversity can result in some of the same long-‐term deficts/problems/health issues as FASD. In those situa,ons it may be difficult if not impossible to separate the effects of FASD from those of early life adversity
§ Animal models can help us sort out these issues
Developmental Origins of Health & Disease (DOHaD)
Adapted from Barker 2000
≤5.5 -6.5 -7.5 -8.5 -9.5 >9.50.0
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Cardiovascular Diseasevs. Birth Weight
Birth Weight (lb)
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Insulin Resistance SyndromePrevalence vs. Birth Weight
Birth Weight (lb)
% w
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Rela,onships between early environment and adult outcomes first published by David Barker and colleagues, who showed correla,ons between low birth weight
and adverse health outcomes (eg., cardiovascular disease, insulin resistance/diabetes) – as birth weight decreased, incidence of disease/disorders increased
How can the intrauterine or early life environment Influence development?
Stress / Infec,on
Maternal Nutri,on / Health
Prenatal Development
Increased Risk for:
• Metabolic Disorders
• Cardiovascular Disease
• Immune Dysfunc,on
• Mental Health Disorders
Postnatal Development
Alcohol / Drugs
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Many things in the environment can influence the developmental trajectory and increase the risk for later life health problems
Fetal Programming Hypothesis: Early life events can program fetal/early life neurobiological/physiological systems, altering
the developmental trajectory and increasing later life vulnerabili9es
Stress / Infec,on
Maternal Nutri,on / Health
Prenatal Development
Fetal Programming
Increased Risk for:
• Metabolic Disorders
• Cardiovascular Disease
• Immune Dysfunc,on
• Mental Health Disorders
Postnatal Development
• Behavior • Cogni,on • Learning • Memory • ADen,on
• Emo,on
Programming or reserng of key hormonal systems by early experience is one mechanism linking early life events with long-‐term health consequences
Alcohol / Drugs
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Programming effects not only physical but also behavioral, cogni,ve, emo,onal
Implica9ons for interven9on § Can we reverse or rescue the programmed phenotype? Evidence suggests that we should be able to intervene to change at least some outcomes
§ Direct mechanisms of alcohol damage -‐ neuronal cell damage/death, inhibi,on of protein/DNA synthesis – may not be reversible
§ But if indirect mechanisms are involved in alcohol’s adverse effects – nutri,on, placenta structure, vascular development, oxida,ve stress/free radicals, growth factors, hormones, cell signaling, cell adhesion, epigene,cs – we might be able to aDenuate these effects o Nutri,on o Drugs that target cell signaling pathways, altered cell adhesion molecules,
epigene,c altera,ons, hormonal changes, inflamma,on, free radicals/oxida,ve stress o Some treatments could act independently, some may be adjunc,ve treatments to boost the
efficacy of current medica,on
o Behavioral interven,ons also very important -‐ may aDenuate adverse effects and improve outcome
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Acknowledgments
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References, cont’d 20. Nguyen et al, Physiol Rep 2:e12087. doi:10.14814/phy2.12087, 2014
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